A group of lymphocytes called natural killer (NK) cells kill many kinds of cells almost indiscriminately. Killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize surface molecules called major histocompatibility complex class I (MHC class I). A major goal of this project is to define the molecular basis of MHC class I recognition by the inhibitory receptors on NK cells. Another important question is how recognition of MHC class I by the receptor results in a negative signal transmitted to the NK cell. Although NK cells serve useful functions in immune responses against certain viruses and parasites, they are dangerous, as they exhibit potent killing activity. Therefore, the mechanisms in place to prevent killing of normal cells by NK cells serve an essential function. It is important to understand how such regulation of NK activity is achieved. Finally, the regulation of NK cell activity by inhibitory receptors serves as a model to study other receptor systems that may use a similar mode of negative regulation. The experiments carried out under this project have defined a region of the receptor that controls recognition of MHC class I, and how the structure of MHC class I molecules may impact on this specific recognition. Some of the early steps in the biochemical pathway of NK cell inhibition have been elucidated. Finally, it was discovered that different inhibitory receptors can block NK activation and that they use distinct signaling pathways to achieve inhibition.